Nitric oxide (NO) is a pluripotent physiological mediator playing a key role in the control number of biological functions. In addition to these essential biological effects, NO has also been shown to be mutagenic in both prokaryotypic and eukaryotic systems. The objective of this project is to assess where the balance lies between these two seemingly paradoxical effects of NO on the carcinogenic process. To study the effects of NO in vivo, transgenic mice have been generated in which the nitric oxide synthase (NOS2) is overexpressed in the mammary gland under the control of the b-casein gene promoter. Immunohistochemical analysis revealed that the NOS2 protein was present in the glandular epithelial cells which is consistant with the location of b-casein production. No histological changes were seen in any organ except the lactating mammary gland in which the alveoli were dilated and the myoepithelial cells flattened. Increased incidence of apoptotic bodies as well as reduced mitotic activity in the mammary gland was associated with the transgenic NOS2 expression. Early results suggest that spontaneous tumor incidence in positive NOS2 transgenic mice after a single pregnancy was not significantly increased.